Various techniques for forming orally administrable edible agents such as drugs, quasi drugs, cosmetics, food, etc. into a shape of a sheet or a film have been proposed. The term “film form” is used herein for generally referring to a shape of a thin layer such as a film or a sheet.
For example, Japanese Patent No. 2559301 discloses production of an orally administrable agent of sheet form by spreading an orally administrable agent preparation solution containing a mixture of a film forming agent, a gel forming agent, an active substance, an inert filler, and a polar solvent on siliconized paper using a coating device, and drying the solution at 80° C. for 10 to 15 minutes, but does not disclose a structure including laminated multiple orally administrable agent layers.
Japanese Patent Laid-Open No. 2001-504106 describes production of an orally administrable agent of film form by coating an orally administrable agent preparation solution on an appropriate carrier material, drying the solution, and then delaminating, or peeling, the obtained orally administrable agent of film form from the carrier material. The carrier material includes a non-siliconized polyethylene terephthalate film, non-siliconized kraft paper, polyethylene-impregnated kraft paper, or a non-silicone polyethylene film, and a knife over roll coating head is preferably used as a coating technique. This document, however, does not teach production of a film orally administrable agent of film form having a structure including laminated multiple orally administrable agent layers.
WO98/56266 and Japanese Patent Laid-Open No. 2002-191343 disclose a method for producing food having a multilayer structure by feeding edible materials of different types and/or blend-ratio into hopper-chambers respectively which are partitioned off a hopper by partition plates, forming a plurality of primary rolled sheets of strip form by a primary common mill roll below the hopper-chambers, superposing the sheets one on another with a certain space therebetween in a direction perpendicular to a longitudinal direction of the sheets during conveyance, and rolling the superposed sheets by a secondary mill roll to bond them to each other. This method is, however, adapted to form a thick multilayer sheet such as cookie dough, pie dough or cracker dough having plasticity by rolling, and cannot produce orally administrable edible agents such as drugs, food, etc. formed by pressure bonding edible materials having a plurality of extremely thin layers of several hundreds μm to several tens thick into a thin multilayer structure having an entire thickness of several thousands μm to several tens μm.
The following is a patent document that relates to obtaining an edible multilayer structure of film form of several thousands μm to several tens μm thick.
For example, Japanese Patent Laid-Open No. 2001-506640 discloses an orally administrable agent of sheet or tape form for administering buprenorphine to oral mucosa, and a producing method for combining a plurality of materials of sheet or tape form coated with an orally administrable agent preparation solution containing buprenorphine so as to form a multilayer material, but does not teach at all a specific method for producing a multilayer structure and a specific producing apparatus for obtaining the multilayer structure.
Further, in the above-described Japanese Patent Laid-open No. 2001-506640, a tape, a sheet, or a foil coated with the orally administrable agent preparation solution and dried is separated as it is by cutting or punching out into a dose or a plurality of doses, and thus delaminating the tape, the sheet, or the foil from the cut piece for administration into the oral cavity is troublesome. When used without the material being delaminated such as the tape, the sheet, or the foil that provides uncomfortable feeling in the oral cavity, the use thereof is restricted and the use is further limited to an inedible material.
Japanese Patent Laid-Open No. 9-235220 discloses an orally administrable agent of film form having a multilayer structure including a drug-containing layer, a non-adhesive layer and an adhesive layer. A producing method thereof disclosed in an embodiment includes repeatedly spreading or spraying an orally administrable agent layer preparation solution on a petri dish made of polytetrafluoroethylene (Teflon®) and delaminating the spread or sprayed orally administrable agent layer preparation solution from the petri dish after drying to obtain an orally administrable agent of film form having a desired multilayer structure. Such a producing method cannot be industrially used, though used in a laboratory. Further, if another orally administrable agent layer preparation solution is manually spread or sprayed on the formed orally administrable agent layer to form a multilayer structure, it is difficult to spread or spray an accurate amount of preparation solution to prevent control of an accurate amount of drug ingredient, and the obtained multilayer orally administrable agent of film form cannot satisfy quantitative accuracy required for pharmaceutical preparations. This document does not teach a producing apparatus at all.
Japanese Patent Laid-Open No. 2001-288074 filed by the applicant of this application proposes a troche (an orally administrable edible agent) of film form including three layers of a covering layer (a), a drug layer I (b), and a drug layer II (c) laminated in order of a-b-c-b-a. This document discloses a method for producing the troche of film form including repeatedly coating and drying each orally administrable edible agent layer preparation solution on a polyester delamination film to form a desired multilayer laminated structure.
In producing the orally administrable edible agent of film form having the multilayer laminated structure described in Japanese Patent Laid-Open No. 2001-288074 filed by the applicant of this application, the applicant uses a coating apparatus 200 for continuously coating and drying the orally administrable edible agent layer preparation solution on a continuously moving resin film as shown in FIG. 1. The coating apparatus 200 guides a resin film 202 set on a resin film unwinding shaft 201 into a drying oven 205 through a nip between a guide roll 203 and a doctor roll 204, and winds up the resin film 202 on a resin film winding shaft 206, thereby continuously moving the resin film 202. In the meantime, an orally administrable edible agent layer preparation solution 208 contained in a dam portion 207 for supplying the orally administrable edible agent layer preparation solution is coated on the resin film, and at this time, a clearance between the resin film 202 on the guide roll 203 and the doctor roll 204 is adjusted to a predetermined dimension to obtain a predetermined coating amount (see the partial enlarged view). A coating layer 208a on the resin film 202 thus formed passes through the drying oven 205 and is dried by hot air uniformly blown from a hot air blowing device 209, and a resin film 210 provided with an orally administrable edible agent layer is wound up on the winding shaft 206 into a roll.
Then, the orally administrable agent layer-formed resin film 210 wound up on the winding shaft 206 into the roll is mounted to the unwinding roll 201 again, the orally administrable edible agent layer preparation solution 208 of the same or different composition is supplied to the dam portion 207 for coating and drying again, and the resin film is wound up on the winding roll 206, thereby producing a resin film including laminated two orally administrable edible agent layers. Repeating such coating and drying steps allows the orally administrable edible agent of film form having a desired multilayer structure to be produced with higher productivity than the conventional methods described above.
However, it has been found that even with the coating method as shown in FIG. 1, accurate control of a coating amount of the orally administrable edible agent layer preparation solution 208 is difficult in producing the orally administrable edible agent of film form having the multilayer structure by repeating the coating and drying steps, and quantitative accuracy required for pharmaceutical preparations cannot be satisfied, like the conventional methods described above.
Specifically, in a first coating step including drying step, the clearance between the doctor roll 204 and the resin film 202 can be set to the predetermined dimension to accurately control the coating amount at a predetermined value. However, a thickness of a dried orally administrable edible agent layer formed in a drying step after the first spreading step varies depending on minor variation of condition of the drying step and environmental conditions such as daily temperature and humidity. Therefore, in a second coating step including drying step, even if the clearance dimension between the doctor roll 204 and the resin film 202 is accurately set, a coating thickness of the second orally administrable edible agent layer further varies depending on variation of the coating thickness of the first orally administrable edible agent layer, since a coating thickness of the orally administrable edible agent layer preparation solution 208 is determined by a clearance between an upper surface of the first dried orally administrable edible agent layer and the doctor roll 204. It is significantly difficult to measure the variation of the thickness of the first edible orally administrable layer 208a after the drying step.
Such an inaccurate coating amount of the orally administrable edible agent layer preparation solution tends to increase as the number of coating steps increases. Further, as the number of coating steps increases, drying time increases. More specifically, drying time for the second orally administrable edible agent layer is 1.5 times longer than that for the first layer, and drying time for a third layer is twice longer than that for the first layer.
In such a situation, in order to obtain an orally administrable edible agent of film form having a multilayer structure including laminated plural thin layers, the applicant attempts to coat and dry an orally administrable edible agent layer preparation solution on a surface of a resin film to produce a resin film provided with an orally administrable edible agent layer having a predetermined thickness, join the resin films together so that orally administrable edible agent layers thereof face each other, pressurize the resin films at back surfaces to pressure bond the orally administrable edible agent layers, and delaminate one of the two resin films sandwiching the bonded orally administrable edible agents.
Then, the orally administrable edible agent having the multilayer structure including laminated plural layers has strength sufficient to form a self-supporting film, and thus the orally administrable edible agent layers adhere to the delaminated resin film to sometimes prevent the orally administrable edible agent layers from being retained on the other intended resin film.
Further, in order to prepare the orally administrable edible agent of film form having the multilayer structure including the laminated plural layers into a predetermined shape, it is efficient that a repeating step of coating, drying and pressure bonding when forming the multiple orally administrable edible agent layers on the surface of the resin film is performed using as wide a resin film as possible, and the resin film is cut into predetermined narrow strips to supply the strips to a preparation step where the strips are punched out into predetermined shapes. However, wildly cutting the wide resin film retaining the orally administrable edible agent layers on the surface thereof into narrow strips may cause distortion, wrinkles or cracks in the orally administrable edible agent layers retained on the resin film.